Cancer kills hundreds of thousands of people every year in the United States alone, and many more cases of cancer are diagnosed each year. Despite advances in the treatment of certain forms of cancer (including surgery, radiotherapy, and chemotherapy), many types of cancer are essentially incurable. Even when an effective treatment is available for a certain cancer, the side effects of such treatment are often severe and can result in a significant decrease in quality of life.
While there are many forms of cancer, all cancers are characterized by inappropriate cell proliferation. Multiple checkpoints are built into the machinery of the cell proliferation cycle where cells make a commitment to commence and accurately regulate DNA synthesis to repair DNA damage or to undergo cell death. Unlike normal cells, cancer cells have lost checkpoint control and have an uncontrolled proliferation drive. The approximately 1016 cell multiplications in the human lifetime, together with inevitable errors in DNA replication and exposure to ultraviolet rays and mutagens, underscores the requirement for checkpoint functions. Major checkpoints occur at G1/S phase and at the G2/M phase transitions where cells make a commitment to repair DNA or undergo apoptosis. Cells are generally thought to undergo apoptosis when DNA damage is irreparable (Li, C J et al. (1999) Proc. Natl. Acad. Sci. USA 96:13369-13374).
Checkpoint kinases (e.g., Chk1, Chk2, and the like) play an important role as a checkpoint in cell cycle progression. Checkpoints prevent cell cycle progression at inappropriate times, such as in response to DNA damage, and maintain the metabolic balance of cells while the cell is arrested, and in some instances can induce apoptosis (programmed cell death) when the requirements of the checkpoint have not been met. Checkpoint control can occur in the G1 phase (prior to DNA synthesis) during S-phase (the replication checkpoint) and in G2, prior to entry into mitosis.
Another important cellular checkpoint is the DNA replication checkpoint, also mediated by CHK1, an essential serine/threonine kinase, which is active during DNA synthesis and functions to coordinate the progression of the cell cycle. Amongst other important functions, the replication checkpoint ensures appropriate control of DNA polymerase progression, order of replication origin firing and suppression of mitosis. In the presence of a replication stress, sufficient to stall replication fork progression, the replication checkpoint becomes critical for maintaining viability, acting to stabilize and preserve the replication fork complexes. Collapse of an active replication fork leads to rapid generation of double strand DNA breaks and cell death. Replication fork collapse is an irretrievable and catastrophic event for a cell.
A primary mechanism of action assigned to DNA antimetabolite drugs, such as cytarabine and gemcitabine, is to suppress DNA synthesis. This is invariably associated with stalled replication forks, activation of the replication checkpoint, and CHK1. CHK1 activity is essential for suppression of DNA damage during exposure to antimetabolites. Cells lacking CHK1 were unable to resume DNA synthesis and subsequently underwent apoptosis. See, e.g., Cho et al, Cell Cycle, 4:1, 131-139 (2005), Syljuåsen R G et al, Mol. Cell Biol., 25(9):3553-62 (2005).
Generically speaking, therapeutic agents that modulate cell cycle checkpoints generally are referred to herein as “checkpoint modulators.” Therapeutic agents that activate cell cycle checkpoint kinases generally are referred to herein as “checkpoint kinase activators.” Therapeutic agents that activate the checkpoint kinase designated “Chk1” (pronounced “check one”) are referred to herein as “Chk1 activators.” Therapeutic agents that activate the checkpoint kinase designated “Chk2” are referred to herein as “Chk2 activators.” Inhibitors of such checkpoint kinases, generally and specifically, are referred to herein as “checkpoint kinase inhibitors”, “Chk1 inhibitors” and “Chk2 inhibitors” and the like. Inhibition of various DNA damage and replication check points therefore is expected to assist in preventing cells from repairing therapeutically induced DNA damage or suppressing replication fork collapse (and other downstream consequences of replication checkpoint activation) and to thus sensitize targeted cells to such therapeutic agents. Such sensitization is in turn expected to increase the therapeutic index of these therapies.
Selective manipulation of checkpoint control in cancer cells could afford broad utilization in cancer chemotherapeutic and radiotherapy regimens and may, in addition, offer a common hallmark of human cancer “genomic instability” to be exploited as the selective basis for the destruction of cancer cells. A number of factors place Chk1 as a pivotal target in DNA-damage and replication checkpoint control. The elucidation of inhibitors of this and functionally related kinases such as CDS1/Chk2, a kinase recently discovered to cooperate with Chk1 in regulating S phase progression (see Zeng et al., Nature, 395, 507-510 (1998); Matsuoka, Science, 282, 1893-1897 (1998)), could provide valuable new therapeutic entities for the treatment of cancer.
Identification of therapeutic agents modulating the checkpoint control may improve cancer treatment. Indeed, recent reports suggest that activation of cell cycle checkpoints may represent an important new paradigm in the treatment of cancer (see, e.g., Y. Li et al., Proc. Natl. Acad. Sci. USA (2003), 100(5), 2674-8). The cell cycle checkpoint activator, beta.-lapachone, which acts at the G1/S phase transition, has been found to exhibit significant anti-tumor activity against a range of tumor types both in vitro and in animal studies while exhibiting a favorable side effect profile, leading to the initiation of human clinical trials. In addition, it has been reported that beta.-lapachone induces necrosis in human breast cancer cells, and apoptosis in ovary, colon, and pancreatic cancer cells through induction of caspase (Li, Y Z et al., Molecular Medicine (1999) 5:232-239).
It has also been reported that beta-lapachone, when combined with Taxol® (paclitaxel; Bristol-Myers Squibb Co., New York, N.Y.) at moderate doses, has effective anti-tumor activity in human ovarian, prostate and breast cancer xenograft models in nude mice. No signs of toxicity to the mice were observed, and no weight loss was recorded during the subsequent two months following treatment during which the tumors did not reappear (See Li, C J et al. Proc. Natl. Acad. Sci. USA (1999) 96:13369-13374). Taxol is believed to act at the G2/M phase transition of the cell cycle.
Commonly-owned WO 2009/061781 published on May 14, 2009, discloses certain novel cell cycle checkpoint modulators. The disclosure of that publication is incorporated herein in its entirety.
Inhibitors of checkpoint kinases are known. For example, commonly assigned US 2007/0083044 and US 2007/0082900, both published Apr. 12, 2007 describes several pyrazolopyrimidines as protein kinase inhibitors, including checkpoint kinase inhibitors and methods of using them. Also, commonly assigned US 2007/0117804 published May 24, 2007 describes several imidazopyrazines as protein kinase inhibitors, including checkpoint kinase inhibitors and methods of using them. Furthermore, S. Ashwell et al, Expert Opin. Investig. Drugs (2008) 17(9): 1331-1340 describe several checkpoint kinase inhibitors, particularly those in development.
Many conventional chemotherapy agents cause damage to cancerous and non-cancerous cells alike. While this broad-spectrum activity allows the chemotherapy to kill many different types of cancers, it often also results in damage to normal cells. The therapeutic index of such compounds (a measure of the ability of the therapy to discriminate between normal and cancerous cells) can be quite low; frequently, a dose of a chemotherapy drug that is effective to kill cancer cells will also kill normal cells, especially those normal cells (such as epithelial cells) which undergo frequent cell division. When normal cells are affected by the therapy, side effects such as hair loss, suppression of hematopoesis, and nausea can occur.
Recent advances in cancer chemotherapeutics have resulted in the development of new “targeted” anti-cancer agents, designed to affect biological targets that are primarily associated with cancerous cells, rather than normal cells. Examples of such agents include imatinib (sold by Novartis under the trade name Gleevec® in the United States), gefitinib (developed by Astra Zeneca under the trade name Iressa®), and erlotinib (sold under the name of Tarceva® by Genentech, OSI, and Roche). While such agents can be quite effective against the intended cellular target, and can have lower rates of side effects than conventional chemotherapies, targeted therapies are, by design, effective only against cells expressing the biological target. Cancer cells which do not express this specific target, or which express a mutated form of the target, may be less affected by a targeted agent. These agents are therefore of limited utility. Researchers have always looked for improved agents.
For example, Gemcitabine (Formula I; 2′,2′-difluoro-2′-deoxycytidine; dFdC) is a pyrimidine analog that has shown activity in various solid tumors,
including non-small cell lung cancer (NSCLC), small cell lung cancer, head and neck squamous cell cancer, germ cell tumors, lymphomas (cutaneous T-cell and Hodgkins' disease), mesothelioma, and tumors of the bladder, breast, ovary, cervix, pancreas, and biliary tract, as well as some hematologic malignancies. The compound was first reported by Lilly Research Laboratories, Eli Lilly and Co.; Indianapolis, Ind. Hertel et al., Cancer Res. 50, 4417-4422 (1990); U.S. Pat. Nos. 4,808,614 and 5,464,826) and sold by Lilly under the trade name, Gemzar®. Gemcitabine is a deoxycytidine analog with structural similarities to cytarabine (Ara-C®).
Gemcitabine is metabolized intracellularly by nucleoside kinases to the active diphosphate (Formula II; dFdCDP) and triphosphate (Formula III; dFdCTP) nucleotide metabolites.
The cytotoxic effect of gemcitabine is generally attributed to the actions of diphosphate and the triphosphate nucleotides, which lead to inhibition of DNA synthesis. Gemcitabine diphosphate (dFdCDP) inhibits ribonucleotide reductase (RNR), which is essential for DNA synthesis and is responsible for catalyzing the reactions that generate the deoxynucleotide triphosphates for DNA synthesis. Inhibition of RNR by the diphosphate nucleotide causes a reduction in the concentration of the deoxynucleotides, including deoxycytidine triphosphate (dCTP). Gemcitabine triphosphate (dFdCTP) competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP (by the action of the diphosphate) further enhances the incorporation of gemcitabine triphosphate into DNA, a process referred to as self-potentiation. After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strand. Further DNA synthesis is inhibited, as DNA polymerase epsilon is unable to remove the gemcitabine nucleotide and repair the growing DNA strand, resulting in what is known as masked chain termination. Gemcitabine induces an S-phase arrest in the cell cycle, and triggers apoptosis in both human leukemic cells and solid tumors. Tolis et al., Eur. J. Cancer, 35, 797-808 (1999). In addition to its cytotoxic effect, gemcitabine is a potent radiosensitizer. Gemcitabine has been investigated as a radiosensitizer for rodent and human tumor cells, including those found in pancreatic, non-small cell lung, head and neck, colorectal, breast, and cervical cancer. Pauwels et al., Oncologist 10(1), 34-51 (2005).
Another known RNR inhibitor is hydroxyurea (HU) or hydroxycarbamide, (Formula IV; brand names include Hydrea® from Bristol-Myers Squibb):
is an antineoplastic drug used in hematological malignancies. Its mechanism of action is believed to be based on its inhibition of the enzyme ribonucleotide reductase by scavenging tyrosyl free radicals.
Combinations of a CHK-1 activator with a CHK-1 inhibitor are disclosed in the past. See, for example, S. Cho et al, Cell Cycle, Vol. 4(1), 131-139 (January 2005), R. Syljuasen et al, Molecular and Cellular Biology, Vol. 25(9), 3553-3562 (2005), as well as the afore-mentioned commonly-owned WO 2009/061781 published on May 14, 2009.
Despite the progress made to date in discovering new anti-tumor treatments, new treatments for cancer are needed.
In an aspect, this invention provides novel compounds and pharmaceutical compositions for the treatment of cancer and precancerous conditions.
In an aspect, this invention provides novel compounds as cell cycle checkpoint modulators and pharmaceutical compositions containing them for the treatment of cancer and precancerous conditions.
In an aspect, this invention provides novel compounds as modulators of cell cycle checkpoints, for example CHk-1, and pharmaceutical compositions containing them for the treatment of cancer and precancerous conditions.
In another aspect, this invention provides methods for treating precancerous conditions or cancer using compounds according to the present invention.
In another aspect, this invention provides methods for treating precancerous conditions or cancer using compounds which modulate cell cycle checkpoints in combination with agents which inhibit checkpoint kinase.
In another aspect, this invention provides methods for treating precancerous conditions or cancer using compounds which activate checkpoint kinases in combination with agents which inhibit checkpoint kinase.